Science Translational Medicine 2010-07-14

Quinone oxidoreductase-2-mediated prodrug cancer therapy.

Mark R Middleton, Richard Knox, Emma Cattell, Udo Oppermann, Rachel Midgley, Raghib Ali, Tim Auton, Roshan Agarwal, David Anderson, Debashis Sarker, Ian Judson, Tsuyoshi Osawa, Victoria J Spanswick, Scot Davies, John A Hartley, David J Kerr

Index: Sci. Transl. Med. 2(40) , 40ra50, (2010)

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Abstract

DNA-damaging agents are widely used in cancer treatment despite their lack of tumor specificity. Human NQO2 (quinone oxidoreductase-2) is an atypical oxidoreductase because no endogenous electron donor has been identified to date. The enzyme converts CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide], in the presence of the synthetic nicotinamide cofactor analog EP0152R, to a cytotoxic bifunctional alkylating agent. NQO2 activity in hepatocellular tumor tissue is higher than that in other cancer types by a factor of 6 and higher than that in bone marrow by a factor of 20. Structural data from x-ray crystallography and nuclear magnetic resonance spectroscopy allowed us to construct a model of CB1954 and EP0152R binding to NQO2, which suggested an optimal infusion schedule for a phase I trial combining the two agents. Thirty-two patients were treated, and diarrhea and serum transaminase concentrations defined a maximum tolerated dose for the drug combination. There was a clear pharmacokinetic interaction, with EP0152R inducing a marked increase in clearance of CB1954, in keeping with model predictions. We detected DNA interstrand cross-links caused by nitroreduced CB1954 in tumor biopsies from treated patients, demonstrating that the activated prodrug exerts its cytotoxic properties through DNA base alkylation.